The goal of this proposal is to identify genes responsible for mendelian neurogenetic disorders in a collection of families that were ascertained, phenotyped and sampled over 30 years at the University of Washington Neurogenetics Clinics and Alzheimer's Disease Research Center. This extensive collection is a valuable resource for the discovery of new genes responsible for neurodegeneration. Our group has had a major role in discovery of genes for neurologic disorders. The disorders for which the causal genes remain to be found present a new challenge, as many of the families are too small to enable positional cloning. Previously there were no methods for gene identification even in families with an extensive history of disease when DNA from only a few affected persons is available. In this proposal we will exploit newly available methods for whole genome detection of rare sequence and copy number variants as a powerful and innovative approach to identify genes involved in neurogenetic disorders. These new techniques include array-based high-resolution comparative genomic hybridization to detect intragenic deletions and duplications, and massively parallel sequencing to detect sequence changes in the protein-coding portion of the genome (the "exome"). Our group of investigators already has substantial experience in applying these novel techniques toward gene identification. We are poised to take maximal advantage of the confluence of infrastructure, our group's expertise in molecular genetics, existing well characterized samples, and advances in array and sequencing techniques that now make it feasible to apply this approach on the whole genome scale. Study of only two affected relatives can reduce the number of candidate genes from 20,000 to several dozen that will then be ranked by function and evaluated in other family members, unrelated cases and controls. For example, we recently published a study in which we used this approach to reduce the number of candidate genes for sensory and motor neuropathy with ataxia (SMNA) from the 300 contained in the large linkage region to one. Although the specific diseases to be investigated herein are not common, the genes and pathways involved may underlie phenotypic differences in and susceptibility to common disorders with which they share clinical features and that are responsible for considerable morbidity. These conditions include Alzheimer's disease, Parkinson's disease, cerebellar ataxia, muscle disease, and peripheral neuropathy, diseases that frequently afflict our aging population. Our innovative approach will likely become the new standard for gene discovery that will enable further advances in the understanding the biology of neurogenetic disorders and identifying targets for therapeutic interventions. ) PUBLIC HEALTH RELEVANCE: The goal of this proposal is to identify novel genes that are responsible for mendelian neurogenetic disorders, including ataxias, neuropathies, myopathies, movement disorders, and highly penetrant familial dementia. We will employ newly available powerful comparative genomic array hybridization, targeted capture and massively parallel sequencing of all protein coding regions in the human genome, and bioinformatics techniques to detect causative mutations in families where the number of available affected persons is too few for linkage analyses. This new approach can rapidly identify the causes of many rare genetic diseases in humans.) )